LINC01116, a hypoxia-lncRNA marker of pathological lymphangiogenesis and poor prognosis in lung adenocarcinoma.

A hypoxic microenvironment promotes the aggressiveness of lung adenocarcinoma (LUAD) through treatment resistance and generation of new lymphatic vessels (i.e., lymphangiogenesis) favoring metastatic dissemination. Transcriptomic analysis of cohorts of LUAD patients highlighted LINC01116, a long noncoding RNA, associated with a bad prognosis, a high rate of recurrence, and induced by hypoxia in tumors. Gain- (overexpression) and loss-of-function (CRISPRi (Clustered Regularly Interspaced Short Palindromic Repeats interference, RNA interference)) approaches performed in LUAD cancer cell lines did not reveal a clear regulatory role for LINC01116 in tumor cells. Analyses of LUAD single-cell RNA sequencing data sets and RNA Fluorescent In Situ Hybridization (RNA-FISH) showed high expression of LINC01116 in lymphatic endothelial cells (LEC) pointing to this transcript as a specific biomarker of tumoral lymphangiogenesis. Efficient knockdown of LINC01116 in LEC in normoxic or hypoxic conditions impacted the proliferation rate under hypoxic stimulation and revealed a gene signature associated with proliferation and hypoxia sensing. Together, our data suggest a role for LINC01116 in pathological lymphangiogenesis of lung tumors.